Eosinophilic esophagitis (EE) is an emerging worldwide disease that mimics gastroesophageal reflux[unreadable] disease (GERD) and chronic esophagitis (CE) and can lead to esophageal narrowing and stricture. EE is[unreadable] differentiated from GERD/CE by the lack of response to acid suppression, and the magnitude of mucosal[unreadable] eosinophilia and epithelial thickening, yet the exact values for the latter two features and molecular markers[unreadable] diagnostic for disease have not been established. Recent attention has been drawn to understanding the[unreadable] etiology and treatment of EE since there has been a surge of newly recognized cases. Employing genome[unreadable] wide microarray expression profile analysis, we recently discovered that the eosinophil chemoattractant and[unreadable] activating factor eotaxin-3 was the single most dysregulated gene in the esophagus of EE patients. Notably,[unreadable] levels of eotaxin-3 strongly correlated with disease severity and a single nucleotide polymorphism (SNP) in[unreadable] the eotaxin-3 gene conferred disease susceptibility. Furthermore, mice harboring a genetic deletion in the[unreadable] eotaxin receptor (CCR3) were protected from the development of experimental EE. These and other[unreadable] findings have led us to hypothesize that a primary event in EE pathogenesis involves overproduction of[unreadable] eotaxin-3 by esophageal (epithelioid-like) cells. In Aim I, we hypothesize that eotaxin-3 will be over-produced[unreadable] in a full spectrum of patients with EE compared with normal individuals. Furthermore, we will test several[unreadable] related sub-hypotheses concerning the cell type(s) that produce eotaxin-3, the relative level of eotaxin-3[unreadable] compared with other eosinophil chemoattractants, and the activity of recombinant eotaxin-3 on eosinophils[unreadable] from EE patients. In Aim 2, we will test the hypothesis that topical glucocorticoid therapy mediates its effects[unreadable] by reducing eotaxin-3 expression. Furthermore, we will determine the genetic transcript signature[unreadable] associated with eotaxin-3 down-regulation and aim to identify a set of gene expression levels that may[unreadable] predict therapeutic responsiveness. In Aim 3, we will test the hypothesis that specific SNPs in the eotaxin-3[unreadable] confer EE disease susceptibility and influence disease phenotype. These studies are aimed to provide[unreadable] mechanistic and diagnostic breakthroughs concerning the pathogenesis of a poorly understood disorder.[unreadable] These studies are timely given the recent attention that EE is receiving in the medical community and the[unreadable] emergence of anti-eotaxin-3/CCR3 therapeutics that may have potential to provide targeted therapy for EE.[unreadable]